Optogenetic hub cell control for no seizures, no side-effects in temporal lobe ep

描述（申请人提供）：颞叶癫痫是成人中最常见的癫痫形式。目前可用的抗癫痫药物往往有显著的和使人衰弱的副作用，而颞叶癫痫经常对药物治疗产生抗药性，提出了一个巨大的社会和医疗问题。这项研究的核心思想是，只有在关键时刻，通过短暂地抑制少数独特神经元的活动，才有可能实现癫痫控制，这些神经元可能是触发边缘系统癫痫发作的主要原因。我们最近的大规模计算模型研究表明，罕见的、异常的、超连接的中枢样神经元可能在癫痫发作中起关键作用。随后，这种中枢细胞在健康发育的海马中得到证实，并且已经表明，在切片中调节单个中枢细胞可以阻断整个网络的自发破裂活动。在这里，我们建议使用新的光遗传学方法来选择性地抑制成年癫痫小鼠齿状回和内嗅皮层中的异常中枢样细胞，以防止在自发性复发癫痫发作时特别在内嗅-海马网络中相互联系通路和时间-氨通路的过度激活。由于这种操作只会以一种暂时选择性的方式影响整个边缘系统中的少数细胞，因此可以在对电路正常信息处理的影响最小的情况下实现有效的癫痫控制。如果成功，这项研究将展示一种全新的方法来实现“无癫痫发作，无副作用”的癫痫治疗目标。

DESCRIPTION (provided by applicant): Temporal lobe epilepsy is the most common form of epilepsy in adults. Currently available anti-epileptic drugs often have significant and debilitating side-effects, and temporal lobe epilepsy frequently becomes resistant to drug therapy, presenting an enormous social and medical problem. The central idea behind the proposed research is that it may be possible to achieve seizure control by transiently inhibiting, only at critical moments, the activity of a low number of unique neurons that may be primarily responsible to triggering seizures in the limbic system. Our recent large-scale computational modeling studies have shown that rare, abnormal, super- connected, hub-like neurons may play a key role in seizure initiation. Subsequently, such hub cells have been demonstrated in the healthy developing hippocampus, and it has been shown that modulation of single hub cells in slices can block the spontaneous bursting activity of the entire network. Here we propose to use novel optogenetic approaches to selectively inhibit abnormal hub-like cells in the dentate gyrus and entorhinal cortex of epileptic adult mice in vivo in order to prevent the hyper-activation of the commissural-associational and temporo-ammonic pathways within the entorhino-hippocampal network specifically at the onset of spontaneous recurrent seizures. Because the manipulation will affect only a few cells in the entire limbic system in a temporally selective manner, effective seizure control may be achieved with minimal effects on the normal information processing of the circuit. If successful, the proposed research will demonstrate a fundamentally novel approach to achieving the goal of "no seizures, no side-effects" for the treatment of epilepsy.